HUMAN GENETICS

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HUMAN GENETICS

• Past
• Present
• Future

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Introduction

• In the past, most of our knowledge about human
  genetics has come from the observation of
  abnormalities with a hereditary pattern trivial
  curiosities.
• Present, information has been from medical
  science to basic genetics.
• Advances in molecular genetics made possible by
  recombinant DNA technology have reached the point
  of practical application in human genetics.

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The Human Karyotype

• Humans have 46 chromosomes
• 44 autosomes and 2 sex chromosomes
• They have a small nucleus and are large in
  quantity
• 1920s cytologists reported finding a diploid
  number of 48 chromosomes
• 1956 techniques for growing cells in tissue
  culture spreading them out for observation
  revealed the correct number.
• Karotype- a graphic representation of the
  chromosomes present in the nucleus of a single
  somatic cell of a particular organism.
• Determines the number, size, and shape of the
  chromosomes
• Identifies the homologous pairs (sometimes
  staining is used to reveal bonding patterns)

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Curtis Barns, 1989
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Essay Preparation of a Karyotype

• Cells in the process of dividing are interrupted
  at metaphase by the addition of cholchicine.
• Treating and staining
• Photographed
• Enlarged
• Cut out
• Arranged according to size
• Certain abnormalities can be detected

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Curtis Barns, 1989
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Chromosome Abnormalities

• Nondisjunction- mistakes during meiosis or
  mitosis, where homologous chromosomes or their
  chromatids may not separate.
• Meiosis nondisjunction
• Gametes with one or more chromosomes too many and
  other gametes with one or more too few.
• Cannot produce a viable embryo and fetus is
  spontaneously aborted early in pregnancy
• Additional Autosomal chromosomes have
  abnormalities (except those with Downs syndrome)
  
• Among those that survive, most are mentally
  retarded and those who survive to maturity are
  usually sterile.
• Deletion- loss of a portion of chromosome
• Translocation- deleted portion of one chromosome
  is transferred to and becomes part of another
  (nonhomologous chromosome)

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Downs Syndrome
http//www.maryslittlelamb.com

• Syndrome- a group of disorder that occur together
  
• People with Downs have short, stocky body type
  with a thick neck, mental retardation, a large
  tongue (speech defects), increase susceptibility
  to infections, abnormalities of heart other
  organs
• Has 3 instead of 2 copies of chromosome 21,
  therefore they have 47 chromosomes
• 95 is caused by nondisjunction
• In translocation- 1/3 of chromosome 21 attaches
  to a large chromosome (often chromosome 14)
• Usually one parent has 45 separate chromosomes (
  chromosome 14 and 21 joined)
• More likely to occur in infants born to older
  women
• 25 of cases are from nondisjunction, the extra
  chromosome comes from the father

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Website with great info http//www.genecrc.org/s
ite/lc/lc2e.htm
library.thinkquest.org/18258/ped-karyo2.htm
library.thinkquest.org/18258/ped-karyo2.htm
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Curtis Barnes, 1989
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Abnormalties of Sex Chromosome

• Nondisjunction
• XY produces maleness
• XXY, XXXY, XXXXY usually sexually
  underdeveloped and sterile
• XXX- sometime produces normal females but almost
  all XXX XO are sterile

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Chromosome Deletions

• Result from congenital defects or other illnesses
• Ex Wilms tumor, deletion of short arm of
  chromosome 11 causes kidney cancer or aniridia.

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Prenatal Detection

• Amniocentesis- prenated detection of Downs
  other genetic conditions in fetus
• Thin needle inserted in mothers abdominal wall
  and through the membrane that eclose the fetus
• A sample of the amniotic fluid (contains living
  cells sloughed off by fetus) ? provide karotype

Curtis Barnes, 1989
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Penylketonuria (PKU)

• Lack the enzyme that converts the amino acid
  phenylalanine to tyrosine
• Phenylalanine abnormal breakdown products
  accumulate in the blood stream urine ? harmful
  to developing nervous system cells which results
  in profound mental retardation
• Caused by recessive allele in homozygous state
• Scientists have enough knowledge to treat? (diet
  containing low amounts of phenylalanine).

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Curtis Barnes, 1989
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Albinism Tay- Sachs

• Albinism- lacks of pigment in skin, hair, and
  eyes ( not able to make brown pigment melanin)
• Either lack enzyme to produce melanin or
• Have the enzyme but is unable to enter pigment
  cells, tryosine is not acted upon melanin is
  not produced
• Inherited as autosomal recessive
• Tay-Sachs- autosomal recessive condition
  resulting in degeneration of the nervous system
• 8 months after birth, symptoms become evident of
  listlessness
• Blindness after the 1st year
• Homozygous individuals lack N-acetyl-hexosaminidas
  e, which breaks down GM2 ganglioside

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Albinism
Tay-Sachs disease
www.mrcpohth.com/iriscases/albinism.html
http//edcenter.med.cornell.edu/CUMC_PathNotes/Neu
ropathology/Neworpath_II/images/4102.jpg
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Tay-Sachs Inheritance
www.sciencemuseum.org.uk/exhibitions/genes/232.asp

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Sickle Cell Anemia

• Originated in Africa
• Due to single amino acid substitution in the beta
  chains of the hemoglobin molecule
• Hemoglobin becomes insoluble and forms bundles of
  stiff fiber when O2 is low ? distort the shape of
  the red blood cells
• Individuals heterozygous for sickle cell are
  symptomless because the good allele makes
  enough normal hemoglobin that the effects of the
  bad allele are not discernable
• No effective treatment is available yet

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www.sunyniagara.cc.ny.us/val/sicklecellhigh.html
www.clevelandclinic.org/health/health-info/docs/00
00/0052.asp?index4579srcnews
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Dwarfs and Other Dominants

• Achrondroplastic dwarfism is caused by dominant
  allele
• Less likely to have children, there is a high
  rate of mutation in genes involved ? condition
  reappears
• Huntingtons disease
• Most familiar autosomal dominant disease
• Destruction of brain cells
• No symptoms of brain cell damage until past 30
  yrs of age

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Sex- linked traits

• 8 of males and .04 of females are colorblind
• The X chromosome carries more genetic information
  affecting color discrimination
• Depends on 3 genes, coding for 3 different visual
  pigments, each responsible to light in different
  regions of the spectrum of visible light
• One responsive to red, green and blue
• Red green are on the X chromosome where as the
  Blue is on the autosomal
• Both X chromosomes carry defective allele ?
  complete red-green color blindness occurs in
  females.

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Curtis Barnes, 1989
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Continued

• Hemophilia- a group of disease in which the blood
  does not clot normally.
• Failure to produce essential plasma protein
  Factor VIII
• Carried on X chromosome
• Muscular Dystrophy
• Group of diseases characterized by muscle wasting
• Common severe type Duchenne- which affects
  cardiac muscle as well as skeletal muscle
• X-linked and appears in males
• Absence of protein in normal muscle cause
  fibrosis, restricted blood supply to muscle cells
• Dystrophin- largest human gene with 2-3 million
  base pairs, including 60 exons and huge introns

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Diagnosis of Genetic Diseases RFLPs

• Sickle Cell
• a person with normal hemoglobin, the probe
  consistently hybridized with a fragment
  7,000-7,600 nucleotides long
• 87 of people with sickle cell was 13,000 long
• RFLPs rif-lips restriction-fragments-length
  polymorphisms- simply inherited variations
  (mutations) in the nucleotide sequences of
  different individuals lead to difference in
  lengths of fragments produced by restriction
  enzymes.
• Studies of Drosophilia confirmed that 2 genes
  that are close together on the same chromosome
  tend to stay together.
• Site for Hpal recognition is altered when the
  beta globin becomes linked with another
  nucleotide sequence
• The closer the allele and its marker, the more
  accurate the diagnosis.

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Continued

• Huntingtons
• Presented a new problem because neither the
  defective gene nor its normal allele had been
  identified- nor have they yet
• Found the marker in a polymorphic restriction
  fragment by cleaving DNA with the restriction
  enzyme Hind III
• 4 different fragments identified (A, B, C, D)
• Huntingtons was associated with pattern A in a
  American family but pattern A was common so it
  did not help to detect
• Was associated with pattern C in a Venezuelan
  family where pattern C was less common

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www.lib.uiowa.edu/hardin/md/huntingtons.html
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www.lib.uiowa.edu/hardin/md/huntingtons.html
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http//web.sfn.org/content/publications/brainbrief
ings/huntingtons.html
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Essay Witness for the Prosecution

• DNA fingerprinting- devised by Alec Jeffrey
• The eukaryotic genome contains many regions of
  simple-sequence DNA, identified short nucleotide
  sequences lined up in the tandem repeated a
  thousand times
• Number of repeated units in such regions differ
  from person to person
• Regions excused from DNA by appropriate
  restriction enzyme
• Placed on an electrophoretic gel
• Separated by length
• Denatured
• Identified by radioactive probe

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Curtis Barnes, 1989
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Diagnosis of Genetic disease radioactive probe

• Used to screen restriction fragments of the human
  genome.
• Thus able to reconstruct the entire gene and
  identify the gene where RFLPs could detect the
  mutations
• Also utilizes short synthetic alleles for normal
  beta globins and sickle cell beta globins
• Another different use is a DNA probe has been
  synthesized that hybridizes with a portion of the
  nucleotide sequence that codes for dystrophin-
  the portion missing in children with the disease.
  The failure to find the complementary fragment
  detects the diagnostic of the disease.

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The Book of Man

• Two fronts in action
• Mapping human chromosomes (involving finding
  marker genes and documenting their rate and
  recombination in breeding population
• The sequencing of the entire genome
• At first, scientist were against it because it
  was expensive and involved the creative talents
  of an entire generation of young scientists
• Opinions shifted when the development of methods
  for automatic sequencing of nucleotides ? this
  decreased the estimate of time and money required
  for the project